1. Field of the Invention
This invention relates to articles of manufacture and to methods for the subungual (under the nail) treatment of infections, especially fungal infections, of the toenails and fingernails (onychomycosis).
2. The State of the Art.
Fungi are eukaryotic cells that may reproduce sexually or asexually and may be biphasic, with one form in nature and a different form in the infected host. Fungal diseases are referred to as mycoses.
A fungal infection of the nails, commonly referred to as onychomycosis, is most frequently caused by dermatophytes but also can be caused by molds and Candida. Mixed infections also occur. Onychomycosis includes dermatophyte infection of the nail by any fungus, including yeast or molds. Thus, for example, onychomycosis serves as a reservoir for dermatophytes and contributes to treatment failure and recurrence of tinea pedis. Most common causes of tinea unguium are Trichophyton rubrum (most frequently), T. mentagrophytes, and Epidermophyton floccusum. These are dermatophytes (fungi that infect hair, skin, and nails) and feed on keratinized (nail) tissue. The nail infections they cause are normally confined to the nail bed and nail plate, but occasionally spread to the surrounding skin. Another type of onychomycosis is caused by yeast (e.g., Candida albicans or Candida parapsilosis). These infections are less common and produce similar symptoms.
The majority of known antifungal agents fall into one of three main groups. One major group includes polyene derivatives, including amphotericin B and the structurally related compounds nystatin and pimaricin, which are only administered intravenously. These are broad-spectrum antifungals that bind to ergosterol, a component of fungal cell membranes, and thereby disrupt the membranes, leading to cell death. Amphotericin B is usually effective for systemic mycoses, but its administration is limited by toxic effects that include fever and kidney damage, and other accompanying side effects, such as anemia, low blood pressure, headache, nausea, vomiting and phlebitis. The unrelated antifungal agent flucytosine (5-fluorocytosine, a diazine), an orally absorbed drug, is frequently used as an adjunct to amphotericin B treatment for some forms of candidiasis and cryptococcal meningitis. Its adverse effects include bone marrow depression with leukopenia and thrombocytopenia.
A second major group of antifungal agents includes azole derivatives which impair synthesis of ergosterol and lead to accumulation of metabolites that disrupt the function of fungal membrane-bound enzyme systems (e.g., CYP-26, i.e., cytochrome P450) and inhibit fungal growth. Significant inhibition of mammalian CYP-26 results in important drug interactions. This group of agents includes ketoconazole (U.S. Pat. Nos. 4,144,346 and 4,223,036), fluconazole (U.S. Pat. No. 4,404,216), itraconazole (U.S. Pat. No. 4,267,179), liarozole, irtemazol, clotrimazole, miconazole, econazole, butoconazole, oxiconazole, sulconazole, and terconazole. U.S. Pat. No. 6,277,873 describes substituted thiazole, thiadiazole, and oxadiazole antifungals.
Antifungal azoles are fungistatic, not fungicidal, which has resulted in azole resistant fungi, that is, fungi strains and isolates which are resistant to treatment with Fluconazole and other known antifungal agents (New Engl. J. Med., 1944, 330:263-272). The small concentration of topical antifungal agents penetrating the nail through to the bed might contribute to the development of fungi resistant to therapeutic agents.
A third major group of antifungal agents includes the fungicidal allylamines such as naftifine (Naftin™), terbinafine (EP 24,587-A1; Lamisil™), and the benzylamine butenafine (Mentax™).
Yet another antifungal is the commonly used thiocarbonate tolnaftate. Like the allylamines and azoles, tolnaftate blocks synthesis of ergosterol.
Various other types of antifungal agents are known. Griseoflulvin is a fungistatic agent which is administered orally for fungal infections of skin, hair or nails that do not respond to topical treatment. U.S. Pat. No. 6,221,903 describes the use of Amiodarone, a Class III antiarrhythnic drug (Amiodarone in Physicians GenRx, 1996, BeDell, et. al., eds., Mosby-Year Book, Inc., St. Louis, Mo.; Amiodarone in Drug Information for the HealthCare Profession, 1997, USP DI, Twinbrook Parkway, Md.; pp. 80-83), as an antifungal agent. Still other antifungal agents include ciclopirox, sulbentine, and morpholines, e.g., amorolfine, and the related morpholines disclosed in U.S. Pat. No. 5,120,530, and the 1-hydroxy-2-pyridone compounds disclosed in U.S. Pat. No. 4,957,730.
It has also been known to combine antifungal agents with anti-inflammatory agents. The steroidal anti-inflammatory agent may be selected from among any of the known steroidal anti-inflammatory agents, including, for example, any of those disclosed in The Merck Index or in U.S. Pat. Nos. 5,002,938, 5,110,809, and 5,219,877. Examples of steroidal anti-inflammatory agents useful in combination with antifungals can include 21-acetoxypregnenolone, alclometasone or its dipropionate salt, algestone, amcinonide, beclomethasone or its dipropionate salt, betamethasone and salts thereof, including, for example, betamethasone benzoate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone sodium phosphate and acetate, and betamethasone valerate; clobetasol or its propionate salt, clocortolone pivalate, hydrocortisone and salts thereof, including, for example, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone phosphate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone tebutate and hydrocortisone valerate; cortisone acetate, desonide, desoximetasone, dexamethasone and salts thereof, for example, acetate and sodium phosphate; diflorasone diacetate, fludrocortisone acetate, flunisolide, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone, methylprednisolone and salts thereof, e.g., acetate, sodium succinate; mometasone furoate, paramethasone acetate, prednisolone and salts thereof, e.g., acetate, diethylaminoacetate, sodium phosphate, sodium succinate, tebutate, trimethylacetate; prednisone, triamcinolone and derivatives thereof, e.g., acetonide, benetonide, diacetate, hexacetonide. Other glucocorticoid steroids reported in the literature, including The Merck Index, or otherwise approved by the local drug regulatory agency, e.g., Food and Drug Administration, may also be used. Preferred steroidal anti-inflammatory agents usually include clobetasol and its salts, e.g., propionate salt; betamethasone and its salts, hydrocortisone and its salts, and triamcinolone and its salts, although as new steroidal anti-inflammatories are developed and reviewed, preferences may change. The anti-inflammatory agent will usually be present in a topical composition in combination with an antifungal in an amount within the range of 0.01 to about 5 percent, preferably from about 0.1 to 2 percent, based on the total weight of the composition.
Thus, various types of antifungal agents and their combination with steroidal anti-inflammatory agents are known.
In spite of the wide varieties of anti-fungal and fungistatic agents, and their use in combination with other active ingredients, onychomycosis is difficult to treat. Since most onychomycosis (i.e., the distal subungual form) is a disease of the nail bed underlying the nail plate, the condition is best treated systemically (from the inside) because topical access to the nail bed is not present. Accordingly, most onychomycosis is treated using oral medications such as terbinafine (Lamisil™) and itraconazole (Sporonox™). The nail grows slowly, and so systemic (oral) medicines require several months for elimination of the infection and regrowth of new nail. These drugs may also produce serious side effects, and they may interact with other medications. Accordingly, systemic medications for treating onychomycosis are unacceptable for many patients. For those patients, the only available route of administration is topical.
Nail lacquers for the treatment of onychomycoses and similar fungal infections affecting nails (toe nails and/or finger nails) of humans, in particular, or other animals, are known. Representative examples are described in the patent literature, such as the following U.S. Pat. No. 4,957,730 (1-hydroxy-2-pyridone in water-insoluble film-former); U.S. Pat. No. 5,120,530 (amorolfine in quaternary ammonium acrylic copolymer); U.S. Pat. No. 5,264,206 (tioconazole, econazole, oxiconazole, miconazole, tolnaftate, naftifine hydrochloride, in water-insoluble film-former); U.S. Pat. No. 5,346,692 (with urea and dibutyl phthalate plasticizer); U.S. Pat. No. 5,487,776 (griseofulvin as colloidal suspension). U.S. Pat. No. 6,224,887, teaches a nail lacquer for onychomycosis with a combination of antifungal and a certain penetration-enhancing medium carbon chain dioxane or acetal. PENLAC™ brand Ciclopirox™ is the only FDA-approved topical treatment approved in the United States for onychomycosis.
Other U.S. patent Nos. which relate to antifungal products include, for example: U.S. Pat. No. 4,636,520 (combination of imidazole and pyrrolnitrin); U.S. Pat. No. 5,002,938 (gel, combination of imidazole and 17-ester corticosteroid anti-inflammatory agent); 5,110,809 (antifungal gel plus steroid); 5,219,877 (gel product with imidazole antifungal optionally with steroidal anti-inflammatory, in a vehicle system that includes lauryl alcohol); U.S. Pat. No. 5,391,367 (aqueous alcoholic gel with tioconazole); U.S. Pat. No. 5,464,610 (salicylic acid plaster); and U.S. Pat. No. 5,696,105 (mometasone furoate).
U.S. Pat. No. 6,207,142 describes antifungal shampoos.
U.S. Pat. No. 5,894,020, discloses an antifungal bar soap for treating tinea pedis.
Anatomically, the “nail” that is seen is technically the nail plate. As shown in FIG. 1, a perspective cross-sectional view of the proximal part of a digit 101, soft tissue 103 overlies the distal phalanx 105 (not shown in other figures), and the majority and distal end of the nail plate 107 overlies the most proximal part of the nail bed 109; the root 111 of the nail plate overlies the nail matrix 113 from which the nail grows. The eponychium 123 (the cuticle) forms a seal between the skin 125 and the proximal end of the nail plate. At the distal end, between the nail plate and the skin, is the hyponychium 127, which is a physical barrier sealing the distal margin of the nail bed where it is coextensive with the nail plate. The nail plate presents a considerable barrier to dorsal (orthogonal) penetration and hence limits access to the nail bed for drugs intended for the nail bed and applied topically to the nail plate. Current topical therapies have such low penetration through the nail plate that they have a very low efficacy (less than 10% even after prolonged application). These therapies do not appear to exhibit characteristic concentration-response or time-response relationships. This suggests that in the small percentage of people in whom these topical treatments are effective, efficacy may not be related to penetration through the nail. Materials such as urea increase the penetration of the medication through the nail plate, but such materials alter the nail and disrupt its integrity.